Project Summary (line 7) This application seeks funding to purchase a 67 megapixel Direct Detection Device (DDD) camera to support 13 users in Southern California with active NIH funding to carry out atomic or near-atomic resolution single particle cryo electron microscopy (cryoEM) studies. The DDD camera will be integrated into an existing, multi- million-dollar Titan Krios cryo electron microscope at the University of California, Los Angeles (UCLA). The critical need for a digital camera capable of recording atomic-resolution cryoEM images of a broad range of biomedically significant macromolecular complexes is justified at multiple levels. This DDD camera will provide essential instrumentation for 13 users that require structure determinations at either atomic or near atomic resolution by cryoEM. Currently, high resolution cryoEM images are recorded with obsolete technology: images are recorded on photographic film that will soon to be unavailable; the films must be scanned, requiring many person-hours and scanners that are already out of production. In addition, film-loading introduces moisture into the microscope column, which contaminates cryoEM samples and reduces usable microscope time (due to pumping out of the column) by a factor of ~2. Of particular note, because users would no longer have to be present at the microscope to load and unload film, they can remotely control the microscope and perform high-resolution cryoEM imaging, thus significantly improving accessibility to this high-end cryoEM instrument for non-UCLA-based users in Southern California, and reducing cost to the users. Indeed, users could send cryoEM grids by overnight service, and, after their grids are loaded by our staff, could image their sample remotely for up to 3 weeks. The 13 users are from leading institutes in Southern California, including UCLA, California Institute of Technology, University of Southern California (USC) and the Scripps Research Institute (Scripps). All of these users are funded by the NIH to pursue research in basic biomedical research, biochemistry, virology and microbiology. All of the projects employ high-resolution cryoEM imaging. Together, the new DDD camera will allow high-resolution cryoEM for a broad range of biological samples from these users, enabling them to understand mechanisms of actions and to identify new targets for the development of new therapeutics. Moreover, the diverse biological structures, with their highly varied architectures, offer a fertile source of data for pushing the limit of high-resolution cryoEM to near 2. These projects are only representative of a potentially much larger pool of projects that could benefit from access to this high-end instrument. Therefore, the installation of the DDD camera in the Titan Krios instrument at UCLA would greatly enhance the access, efficiency and thus reduce cost of these users and potentially new users from all over the world.